This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector expressing alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency. Three groups of three subjects each will receive the study drug by intramuscular injection, with progressively larger doses in the second and third groups.

The change in serum M-specific alpha-1 antitrypsin concentration was calculated as the difference between the mean values at the screening and baseline visits and the mean values at the 6, 9 and 12 month visits. The standard error of the difference was calculated as sqrt(s1^2/n1 + s2^2/n2, where s1 is the standard deviation of the baseline mean, s2 is the standard deviation of the month 6-12 mean, n1 is the number of baseline values and n2 is the number of month 6-12 values.

The change in serum total alpha-1 antitrypsin concentration was calculated as the difference between the mean values at the screening and baseline visits and the mean values at the 6, 9 and 12 month visits. The standard error of the difference was calculated as sqrt(s1^2/n1 + s2^2/n2, where s1 is the standard deviation of the baseline mean, s2 is the standard deviation of the month 6-12 mean, n1 is the number of baseline values and n2 is the number of month 6-12 values.

The study is a non-randomized, open-label, multi-center, sequential, three-arm, Phase 2 clinical trial evaluating the safety and efficacy of administration of a rAAV1-CB-hAAT vector administered by IM injection. Each participant will receive rAAV1-CB-hAAT on a single occasion. Three groups of three subjects each will receive rAAV1-CB-hAAT at dosage levels of 6 x 10e11 vg/kg, 1.9 x 10e12 vg/kg or 6 x 10e12 vg/kg by IM injection. Subjects in group 1 will receive a total of 10 IM injections distributed across a single muscle site, subjects in group 2 will receive a total of 32 IM injections distributed across three muscle sites, and subjects in group 3 will receive 100 IM injections distributed across 10 muscle sites. Each injection will be given in a volume of 1.35 mL, at the appropriate vector concentration to achieve the desired total vector dose, and the injection density at each administration site (nine IM injections per 4 cm2 skin surface area) will be the same as the injection density that was well tolerated in a previous Phase 1 clinical trial with rAAV1-CB-hAAT. Safety will be monitored by evaluation of adverse events, hematology and clinical chemistry parameters, histological examination of muscle biopsies, and measurement of serum antibodies to AAT. Efficacy will be measured by evaluation of serum concentrations of M-specific AAT and total AAT and serum AAT phenotype determined on isoelectric focusing gels. Additional information to be collected will include presence of the vector in blood or semen, changes in serum anti-AAV antibody titers, and changes in T cell responses to AAV and AAT.

Eligibility

Ages Eligible for Study:

18 Years to 75 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Have a diagnosis of AAT-deficiency, as defined by a serum AAT level of less than 11 µM and a phenotype or genotype either homozygous for PI*Z or compound heterozygous consisting of PI*Z and another allele known to be associated with disease

Be at least 18 and not more than 75 years of age

Have a FEV1 >25% of predicted value (post bronchodilator)

Weigh ≤ 90 kg

Not receiving AAT augmentation therapy currently or with the past 3 months, and not planning to begin such therapy for at least 12 months after administration of rAAV1-CB-hAAT

Be willing to discontinue aspirin, aspirin-containing products, and other drugs that may alter platelet function, 7 days prior to dosing, resuming no earlier than 24 hours after the dose has been administered

Have acceptable laboratory parameters

For females of childbearing potential:

A negative pregnancy test (urine or serum) at screening and at baseline (within 2 days before administration of study agent)

Agreement to consistently use barrier contraception (condoms, diaphragm or cervical cap with spermicide) or another form of contraception (e.g. intrauterine device or hormonal contraception) from the screening visit until 12 months after administration of rAAV1-CB-hAAT, for sexual activity that could lead to pregnancy

For males of reproductive potential, agreement to consistently use barrier contraception (condoms with spermicide) for 12 months after administration of rAAV1-CB-hAAT, for sexual activity that could lead to pregnancy,

Provide signed informed consent before screening

Exclusion Criteria:

Prior receipt of any AAV gene therapy product

Use of anticoagulants or anti-platelet agents within 7 days prior to study agent administration

History of immune response to human AAT augmentation therapy as indicated by clinical history of an adverse immune response to infusion and/or decreased therapeutic effect in combination with documentation of serum anti-AAT antibodies

Use of acute oral or intravenous antibiotic therapy for a respiratory infection within 28 days prior to study agent administration (long-term maintenance or chronic suppressive oral antibiotics, and antibiotics for a non-respiratory indication, are allowed)

Use of oral or systemic corticosteroids within 28 days prior to study agent administration

Use of any investigational agent, or any immunosuppressive drug(s), within 3 months prior to enrollment

For females of childbearing potential, a positive pregnancy test at screening or baseline (within 2 days before rAAV1-CB-hAAT administration)

Have had pulmonary edema or a pulmonary embolism within the past 6 months

Have a history of immunodeficiency or other medical condition which leads the investigator to believe that the participant cannot comply with the protocol requirements or that may place the participant at an unacceptable risk for participation

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01054339